Inflammatory bowel diseases (IBDs) are caused by an aberrant and excessive local immune response to components of bacterial microflora (Bouma G and Strober W. Nat. Rev. Immunol. 3: 521-533, 2003) and is controlled by regulatory molecules, including TGF-beta1 (Kulkarni A. B. and Karlsson, S. Am. J. Pathol. 143: 3-9, 1993). Disruption of TGF-beta1 signaling occurs in IBDs by the upregulation of the intracellular inhibitor of Smad signaling, Smad7 (Nakao A et al. Nature 389: 631-635, 1997); one of the main pathological processes involved in the tissue-destructive inflammatory response of IBDs in humans. Therefore, therapeutics that reduce Smad7 protein or function may restore TGF-beta1 signaling and reset immune homeostasis.
The current standard of medical care for Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease in humans, involves treatment with anti-inflammatory agents, corticosteroids, immunomodulators, including azathioprine, or its active metabolite 6-mercaptopurine, methotrexate, biologic agents, including tumor necrosis factor antagonist therapies, anti-integrin therapies, and anti-interleukin (IL) 12/23 therapy. Recently, antisense inhibition of Smad7 by a morpholino oligonucleotide in animal models as well as in patients with Crohn's disease has been demonstrated (Monteleone et al. Mucosal Immunol. 1: S50-S53, 2008; Monteleone et al. N. Engl. J. Med. 372: 1104-1113, 2015). It is an object herein to provide compounds and compositions of high efficacy and tolerability for the treatment of diseases disclosed herein.